Reversal of Inhibition/Induction

Excerpt from Cafer's Mood Stabilizers and Antiepileptics

REVERSAL OF ENZYME INHIBITION/ INDUCTION

All things being equal, it is best to avoid prescribing strong inducers or inhibitors. Even if there is no problematic interaction at the time, having a strong inhibitor or inducer on board may complicate future medication management. 

Consider an individual on an established medication regimen who stops taking an inducer or inhibitor. The serum concentration of victim substrate(s) will change due to the reversal of induction/inhibition.

After an inDucer is withdrawn, the concentration of a victim substrate will increase gradually (D for Delayed) over a few weeks because the extra CYP enzymes are degraded without being replenished.

When an inHibitor is stopped, levels of a victim substrate will decrease as soon as the aggressor exits the body. “Hurriedly” does not mean immediately, because it takes about five half-lives for a drug to be completely cleared. 

For a patient on several psychotropic medications, reversal of inhibition or induction can really throw things out of whack.

While ePrescribe systems may warn the doctor when starting an interacting medication, there will be no warning when stopping a medication will lead to a reversal situation.

An example of reversal of inDuction involves tobacco, which is a 1A2 inDucer. A patient taking clozapine (1A2 substrate) stops smoking, reversing inDuction and causing clozapine levels to potentially double over the first week (which is faster than occurs with other inducers). The individual may become obtunded, hypotensive, or even have a seizure. To avoid this, the recommendation is to decrease clozapine dose by 10% daily over the first four days upon smoking cessation, and to check clozapine blood levels before and after the dose adjustment. Note that nicotine products (gum, patches, e-cigs) do not induce 1A2.

Consider a patient taking alprazolam (Xanax, 3A4 substrate) who suddenly stops fluvoxamine (Luvox, 3A4 inHibitor). In absence of the inhibitor, alprazolam levels drop (from double) to normal. Since fluvoxamine has a short elimination half-life of 15 hours, it should be out of the body at 75 hours (15 hr x 5). So, you would expect the patient on Xanax to become more anxious 3 days after stopping Luvox. It may be difficult to discern whether the patient’s emerging distress is due to serotonin withdrawal or decreased alprazolam levels. 

Although reversal of inHibition is typically faster than reversal of induction, this does not apply to inhibitors with extremely long half-lives. For instance, fluoxetine (Prozac) has a long elimination half-life of about 7 days, keeping itself around for about 35 days (7 days x 5). Consider a patient with schizophrenia on aripiprazole (Abilify, 2D6 substrate) who stops Prozac (2D6 inHibitor). The patient is doing well at one month, but becomes paranoid two months out. Unless the prescriber anticipated this possibility, no one will realize what happened.

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